Tuberculosis is a major public health problem, with the emergence of resistance to existing drugs posing a significant challenge to modern therapy. One of the promising new therapeutic approaches is targeting the enzyme enoyl-ACP-reductase (InhA), which plays an important role in the process of biosynthesis of mycolic acids that are crucial for the cell wall of the Mycobacterium tuberculosis, the causative agent of tuberculosis. The aim of this thesis was the synthesis and biochemical evaluation of new potential InhA enzyme inhibitors with thiourea and phenolic structures.
Based on data received from previous molecular docking studies, we synthesised several new compounds through multistep synthetic pathways. In the process we included the introduction and removal of protecting groups, formation of amide bonds, synthesis of thiourea derivatives and the application of different reaction conditions such as microwave-assisted reactions. We monitored the progress using thin-layer chromatography (TLC) along with liquid chromatography coupled with mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) analysis. We confirmed the structure of final products using different analytical methods. During synthesis we faced several challenges, such as low yields, poor solubility and the formation of side products. However, we successfully isolated and characterized nine compounds that underwent biochemical evaluation in vitro.
Biological testing showed that the synthesized product did not exhibit significant inhibitory activity against the InhA enzyme, since high residual activity was observed. Despite no activity showed, our results contribute to a better understanding of the structure-activity relationship, providing information for future optimization in the development of new, more effective InhA inhibitors.
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